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Alloimmunisation against paternal human platelet antigen (HPA) can result in fetomaternal alloimmune thrombocytopenia (FMAIT) and intracranial haemorrhage (ICH) in the fetus, both in the antenatal and perinatal period. Analysis of 200 confirmed cases of FMAIT, showed that HPA-1a antibodies accounted for 75% of all cases and ICHs, with long-term neurological disabilities in 72%. Clinical data showed that antenatal treatment of alloimmunised pregnancies with intrauterine transfusions (lUT) carried a 15% risk of intrauterine death (lUD) and that postnatal treatment with HPA-1a negative platelet was effective but not used consistently.

The rich behavioural repertoire of the fetus provides a means of assessing central nervous system integrity, and thus the well-being of the fetus. Pregnancy in women with epilepsy is associated with a higher risk of congenital malformation and long-term developmental delay. The cause of these risks is thought to be the anti-epileptic drugs that women with epilepsy continue to take during pregnancy to prevent seizures. This thesis, using fetal behaviour as a diagnostic tool, studied the effect of the anti-epileptic drugs; Carbamazepine, Lamotrigine and Valproate on the fetal behaviour. The spontaneous behaviour and the habituation response of the fetus were examined at 12- 15, 18-22, 31 and 37 weeks of gestation in two groups of mothers; those mothers with epilepsy taking anti-epileptic drugs and a control group of mothers not having epilepsy and thus not taking anti-epileptic drugs. Further analyses examined the effects of the specific drug; mothers were taking Carbamazepine, Lamotrigine or Valproate with a group of mothers not taking anti-epileptic drugs. There was a significant difference between the fetuses in the Carbamazepine group and the control group higher at 12-15 weeks gestation. Total activity was significantly higher in the Carbamazepine group compared with fetuses not exposed to anti-epileptic drugs. Mean mouth movement scores were significantly lower at 18-22 weeks in fetuses exposed to Carbamazepine. Habituation performance was significantly different for the fetuses exposed to Carbamazepine at 31 weeks gestation. The . fetuses exposed to Carbamazepine showed a poorer habituation performance. Postnatally children who had been exposed Valproate scored significantly lower in both the mental and psychomotor developmental index scores of the Bayleys scale of Infant Development than children who had not been exposed to anti-epileptic drugs. Anti-epileptic drugs were observed to affect the behaviour of the fetus, suggestive of an effect on the central nervous system.

Fetal macrosomia is associated with maternal and neonatal morbidity. Aims of thesis: • Systematically review the evidence in relation to physical activity, maternal nutrition and macrosomia • Conduct a prospective cohort study (Phase 1) exploring physical activity and maternal nutrition as potentially modifiable risk factors for fetal macrosomia • Conduct a qualitative study (Phase 2) using semi structured interviews to explore women's experiences of delivering a large for gestational age infant. Methods Population: Low risk pregnant women predicted to deliver macrosomic babies (study group) or appropriate for gestational age (AGA) babies (control group). Phase 1: Participants wore a SenseWear® physical activity armband and completed a food diary (four consecutive days) in the third trimester of pregnancy. Demographic and obstetric data were collected from maternity records. Phase 2: Interviews were conducted at 3-4 months postpartum with a subgroup of women who delivered macrosomic babies. Results 112 women participated in the study. Women who delivered macrosomic babies (≥4000g) spent significantly more time at very low levels of physical activity <1 MET) than other women (p=0.007). Intake of PUFA n-3 was significantly higher in women who were predicted to deliver macrosomic babies but delivered AGA babies at full term of this pregnancy (p=0.015). Women predicted to deliver macrosomic babies were more likely to be overweight (BMI> 25 kg/m-) at booking (p=O.017) and have attained third level education (p=0.024). Predicted macrosomia was strongly associated with Caesarean section (p=0.10) compared with the control group (43%vs22%). Experiences of delivering a macrosomic baby are influenced by previous experiences, relationships with health professionals and personal perceptions of macrosomia. Conclusion Findings from this study provide evidence that a more sedentary maternal lifestyle during the third trimester of pregnancy is associated with macrosomia. The evidence from this study forms the basis for future research and has implications for both practice and public health policy.

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Fetal growth restriction is the failure of a fetus to achieve its full growth potential, resulting in a neonate that is small for its gestational age. The aetiology of fetal growth restriction is varied and fetal growth restriction secondary to placental insufficiency is attributed to a failure of trophoblast invasion leading to under perfusion of the uteroplacental bed. In response to the adverse conditions in-utero, fetuses tend to compensate by increasing blood flow to the essential organs such as the brain, heart, and adrenals, at the expense of other organs (cerebral redistribution). As a consequence, growth tends to be asymmetric, with maintenance of the head growth velocity while the other growth parameters tail off; an effect which is also known as the ‘brain sparing effect’. Despite this apparent brain sparing effect, children who were growth restricted in utero are at increased risk of developmental delay and behavioural problems. 30 growth restricted and 48 normally grown fetuses were recruited into this study and were imaged using both conventional ultrasound with Doppler assessment, as well as fetal MRI with ssFSE sequences through the feto-placental unit and fetal brain. A dynamic approach was taken when imaging the fetal brain to compensate for the presence of fetal motion. MR imaging of the feto-placental unit detected significant differences in placental appearance, significantly smaller volumes of intra-abdominal and intra-thoracic organs, and significantly smaller regional brain growth among growth restricted fetuses. MR studies of the placenta in fetal growth restriction demonstrated a placental phenotype in growth restricted pregnancies that is characterised by smaller placental volumes, a significant increase in the placental volume affected by apparent pathology on MRI and a thickened, globular placenta. Although placental volume increased with gestation in both groups, the placental volume remained significantly smaller in the growth restricted fetuses (p = 0.003). There was also a significant correlation between the percentage of placental volume affected by abnormal heterogeneity and the severity of fetal growth restriction (r = 0.82, p < 0.001), and an increase in the maximal placental thickness to placental volume ratio above the 95th centile for gestational age was associated with fetal and early neonatal mortality (relative risk = 7, 95%CI = 2.96 – 16.55, p < 0.001) (figure 3.6) MR studies of fetal intra-thoracic and intra-abdominal volumes showed that although the volume of the intra-thoracic and intra-abdonimal organs (heart, lungs, thymus, liver and kidney) increased as gestation increased in both groups, the volumes of all three structures remained smaller in growth restricted fetuses (p < 0.01) (Figures 4.7 - 4.9) compared with normally grown fetuses. MR studies of the fetal brain demonstrated smaller intracranial volume, total brain volume and cerebellar volume in growth restricted fetuses. In addition, growth restricted fetuses with early onset fetal growth restriction demonstrated smaller vermis height and a corresponding increase in the tegmento-vermian angle. Growth restricted fetuses also demonstrated a disproportionate decrease in extra- and intra-cerebral fluid. This thesis showed evidence of changes in regional and global organ growth in growth restricted fetuses using high resolution fetal MRI. It is hoped that future imaging studies could offer useful insights into the origins and clinical significance of these findings and its consequences for later neurodevelopment.